Selective translational repression of HIV-1 RNA by Sam68DeltaC occurs by altering PABP1 binding to unspliced viral RNA.
HIV-1 structural proteins are translated from incompletely spliced 9 kb and 4 kb mRNAs, which are transported to the cytoplasm by Crm1. It has been assumed that once in the cytoplasm, translation of incompletely spliced HIV-1 mRNAs occurs in the same manner as host mRNAs. Previous analyses have demonstrated that Sam68 and a mutant thereof, Sam68DeltaC, have dramatic effects on HIV gene expression, strongly enhancing and inhibiting viral structural protein synthesis, respectively. While investigating the inhibition of incompletely spliced HIV-1 mRNAs by Sam68DeltaC, we determined that the effect was independent of the perinuclear bundling of the viral RNA. Inhibition was dependent upon the nuclear export pathway used, as translation of viral RNA exported via the Tap/CTE export pathway was not blocked by Sam68DeltaC. We demonstrate that inhibition of HIV expression by Sam68DeltaC is correlated with a loss of PABP1 binding with no attendant change in polyadenosine tail length of the affected RNAs. The capacity of Sam68DeltaC to selectively inhibit translation of HIV-1 RNAs exported by Crm1 suggests that it is able to recognize unique characteristics of these viral RNPs, a property that could lead to new therapeutic approaches to controlling HIV-1 replication.
Marsh
Kim
K
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. kim.marsh@utoronto.ca
Soros
Vanessa
V
Cochrane
Alan
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects*; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; D039122:Poly(A)-Binding Protein I; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D014764:Viral Proteins